The invention relates to the targeted delivery of substances to cells.
Delivery of substances to cells allows specific treatment of the cells with compounds that act in the targeted cell. For example, tumor cells, when targeted with toxic components, selectively die when the toxin is delivered to the cell. Yet other cells, when provided with a gene lacking in the cell, can be restored in their function, which is so-called xe2x80x9cgene therapyxe2x80x9d.
Delivery of a compound to a cell preferably occurs with a vehicle or particle that effectively brings the compound to the desired cell or cells and then delivers the compound into that cell (in vivo or in vitro) where it can exert its action. For this purpose, particles such as virus-like particles are suited. These particles, often derived from known viruses, such as retrovirus or adenovirus, are small enough to penetrate in-between tissues and cells and arrive at a cell of choice where it can, for example, fuse with the cell and deliver its compound. The virus-like particles may or may not be infectious in themselves; their main concern is the targeted delivery of the compound of interest, such as a gene, a toxin or immuno-stimulating components such as antigens.
Yet other examples are gene-delivery vehicles, specifically designed to transfer a gene to a cell of interest. Virus-like particles capable of delivering a gene are examples of gene-delivery vehicles; however, other examples of such vehicles, of non-viral origin, exist, such as liposomes or microbodies, or even latex particles. Vehicles such as liposomes or microbodies can, of course, also carry compounds other than a gene; in particular, toxic or immuno-stimulating components such as antigens can be included in such a vehicle.
These vehicles or particles all have in common that they are provided with a molecule or fragment thereof (ligand) capable of binding with the targeted cell, allowing targeting of the particle or vehicles to cells. A need exists for specific or broadly applicable ligands that react with cell-surface receptors on cells. In particular, a need exists for ligands that react with cell-surface receptors after which efficient transfer of the compound to the cell, such as a gene, is possible. Especially in human medicine, such a ligand would enable better application of gene-transfer therapy than is possible now.
It has been a long-standing objective to exploit retrovirus technology in human gene therapy applications. However, the infection spectrum of retroviruses limits the applications of these viruses in such applications. All known env variants have a rather broad infection spectrum in common. Herein lies one of the major shortcomings of current recombinant retrovirus technology. For the purpose of gene therapy, retroviruses are very useful vehicles for the transfer of therapeutic sequences if proper ligand-receptor targets are available.
In conclusion, the concept of the use of retroviruses in human gene therapy is well documented (Gordon and Anderson, 1994; Havenga et al., 1997; Vile et al., 1996). However, it would be clearly advantageous and desirable to devise a strategy for targeted delivery of retroviruses, and modification of the infection spectrum.
The invention relates to the targeted delivery of substances to cells. Specifically, the invention includes a virus-like particle or gene delivery vehicle provided with a ligand capable of binding to a human amino acid transporter. Included are, for example, ligands that can bind to the human transporter of cationic L-amino acids (xe2x80x9chCAT1xe2x80x9d). Such hCAT1 binding molecules find applications in the design of vector systems for entry into, for example, human or primate cells. Preferred are retroviral envelope molecules, whichxe2x80x94when incorporated in a virus particlexe2x80x94can infect hCAT1 positive cells at high frequencies. The invention also includes methods for the design of such hCAT1 binding molecules.